We propose to further characterize the HLA-D and HLA-DR loci within the Major Histocompatability Complex (MHC) of man. We wish to determine whether these are separate and distinct loci or whether they represent the same locus as assayed by very different technologies (i.e. cellular versus serological). We will accomplish this goal by (1) refining existing methodologies for HLA-D and HLA-DR typing, (2) completing HLA-DR typing on previously HLA-D typed donors, (3) testing data against a model that HLA-D/DR may exist as two stable duplicate genes coding for identical alleles, consistent with the concept that the entire MHC evolved by gene duplication. Family studies will be performed in order to follow the segregation of specific D/DR allelic determinants and with the anticipation that recombinants may be identified that will assist in the mapping of the MHC and, especially, in characterizing the relationship between these two putative loci. The families selected for study will be those with familial cancer syndromes, chromosomal instability syndromes, large high-risk cancer pedigrees and families with immunodeficiency and cancer. In this way, we hope to utilize our family data for the secondary goal of identifying cancer susceptibility genes (CSGs) as well. Selected members of such families who appear to either express or carry CSGs will be studied more intensively for immune status, DNA repair mechanism, immunodeficiency-related, enzyme levels, erythrocyte markers and karyotyping.